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Importance: National Comprehensive Cancer Network guidelines recommend weekly cisplatin as an alternative concurrent systemic therapy for definitive chemoradiation in patients with head and neck cancer. However, the impact of different levels of adherence to weekly cisplatin on outcomes stratified by human papillomavirus p16 status remains unclear., Objective: To evaluate the association between the number of weekly cisplatin cycles and outcomes., Design, Setting, and Participants: This retrospective, observational, single-institution cohort study at The Ohio State Comprehensive Cancer Center included patients with a diagnosis of nonmetastatic head and neck cancer between December 1, 2011, and March 30, 2020, who received chemoradiation. Data analysis was performed between March and May 2024., Exposure: A total of 5, 6, or 7 to 8 weekly cisplatin cycles., Main Outcomes and Measures: The primary outcomes were overall survival (OS), progression-free survival (PFS), locoregional failure (LRF), and distant failure (DF). Cox multivariable analysis was performed for variables associated with OS and PFS, and Fine-Gray multivariable analysis was performed for variables associated with LRF and DF., Results: A total of 142 patients met the criteria (119 men [83.8%]; median [IQR] age, 59 [54-63] years). Median (IQR) follow-up was 46.8 (40.8-55.6) months. Among 92 patients with reasons for cisplatin interruption reported, the most common reason was low blood counts (42 patients [45.7%]). Those who missed weekly cisplatin cycles had worse OS (adjusted hazard ratio [aHR], 2.22; 95% CI, 1.19-4.17; P = .01) and PFS (aHR, 1.83; 95% CI, 1.06-3.15; P = .03) than those who received 7 to 8 cycles. Cancer control outcomes were comparable between these groups (LRF aHR, 0.53; 95% CI, 0.15-1.93; P = .34; DF aHR, 1.51; 95% CI, 0.60-3.82; P = .38). Patients with p16-negative tumors who missed weekly cisplatin cycles had worse OS (for every missing cisplatin cycle, aHR, 11.34, 1.51-84.94; P = .02) than those treated with 7 to 8 cycles. However, for those with p16-positive tumors, there were no statistically significant differences in OS between those who missed weekly cisplatin cycles vs others who received 7 to 8 cycles (aHR, 1.21; 95% CI, 0.47-3.14; P = .69)., Conclusions and Relevance: In this cohort study of patients with head and neck cancer who received definitive chemoradiation, those with p16-negative tumors who missed weekly cisplatin cycles had lower OS than those who received 7 to 8 cycles, although OS was comparable between these groups for p16-positive tumors. Cytopenia represented the most common reason for cisplatin interruption.

Background: Despite recommendations for upfront total laryngectomy (TL), many patients with cT4a laryngeal cancer (LC) instead undergo definitive chemoradiation, which is associated with inferior survival. Sociodemographic and oncologic characteristics associated with TL utilization in this population are understudied., Methods: This retrospective cohort study utilized hospital registry data from the National Cancer Database to analyze patients diagnosed with cT4a LC from 2004 to 2017. Patients were stratified by receipt of TL, and patient and facility characteristics were compared between the two groups. Logistic regression analyses and Cox proportional hazards methodology were performed to determine variables associated with receipt of TL and with overall survival (OS), respectively. OS was estimated using the Kaplan-Meier method and compared between treatment groups using log-rank testing. TL usage over time was assessed., Results: There were 11,149 patients identified. TL utilization increased from 36% in 2004 to 55% in 2017. Treatment at an academic/research program (OR 3.06) or integrated network cancer program (OR 1.50), male sex (OR 1.19), and Medicaid insurance (OR 1.31) were associated with increased likelihood of undergoing TL on multivariate analysis (MVA), whereas age > 61 (OR 0.81), Charlson-Deyo comorbidity score ≥ 3 (OR 0.74), and clinically positive regional nodes (OR 0.78 [cN1], OR 0.67 [cN2], OR 0.21 [cN3]) were associated with decreased likelihood. Those undergoing TL with post-operative radiotherapy (+/- chemotherapy) had better survival than those receiving chemoradiation (median OS 121 vs. 97 months; p = 0.003), and TL + PORT was associated with lower risk of death compared to chemoradiation on MVA (HR 0.72; p = 0.024)., Conclusions: Usage of TL for cT4a LC is increasing over time but remains below 60%. Patients seeking care at academic/research centers are significantly more likely to undergo TL, highlighting the importance of decreasing barriers to accessing these centers. Increased focus should be placed on understanding and addressing the additional patient-, physician-, and system-level factors that lead to decreased utilization of surgery.

Background: Racial/ethnic (R/E) minorities with head and neck squamous cell carcinoma (HNSCC) have worse survival outcomes compared to White patients. While disparities in patient outcomes for R/E minorities have been well documented, the specific drivers of the inferior outcomes remain poorly understood., Patients and Methods: This was a population-based retrospective cohort study that analyzed HNSCC patients using the National Cancer Database (NCDB) from 2000-2016. Patient outcomes were stratified by R/E groups including White, Black, Hispanic, Native American/Other, and Asian. The main outcome in this study was overall survival (OS). Univariate time-to-event survival analyses were performed using the Kaplan-Meier product limit estimates and the log-rank test to evaluate the differences between strata., Results: There were 304,138 patients with HNSCC identified in this study, of which 262,762 (86.3%) were White, 32,528 (10.6%) were Black, 6191 were Asian (2.0%), and 2657 were Native American/Other (0.9%). Black R/E minorities were more likely to be uninsured (9% vs. 5%, p < 0.0001), have Medicaid insurance (22% vs. 8%, p < 0.0001), be in a lower income quartile (<30,000, 42% vs. 13%, p < 0.0001), have metastatic disease (5% vs. 2%, p < 0.001), and have a total treatment time 6 days longer than White patients (median 107 vs. 101 days, p < 0.001). The 5-year OS for White, Black, Native American/Other, and Asian patients was 50.8%, 38.6%, 51.1%, and 55.8%, respectively. Among the oropharynx HNSCC patients, the 5-year OS rates in p16+ White, Black, and Asian patients were 65.7%, 39.4%%, and 55%, respectively. After a multivariate analysis, Black race was still associated with an inferior OS (HR:1.09, 95% CI: 1.03-1.15, p = 0.002)., Conclusions: This large cohort study of HNSCC patients demonstrates that Black race is independently associated with worse OS, in part due to socioeconomic, clinical, and treatment-related factors.

Purpose: To determine the magnitude of MRI image distortion based on 6 consecutive years of annual quality assurances/measurements on 14 MRI scanners used for radiation therapy and to provide evidence for the inclusion of additional margin for treatment planning., Methods and Materials: We used commercial MRI image phantoms to quantitatively study the MRI image distortion over period of 6 years for up to 14 1.5 and 3 T MRI scanners that could potentially be used to provide MRI images for treatment planning. With the phantom images collected from 2016 to 2022, we investigated the MRI image distortion, the dependence of distortion on the distance from the imaging isocenter, and the possible causes of large distortion discovered., Results: MRI image distortion increases with the distance from the imaging isocenter. For a region of interest (ROI) with a radius of 100 mm centered at the isocenter, the mean magnitude of distortion for all MRI scanners is 0.44 ± 0.18 mm $0.44 \pm 0.18\;{\rm{mm}}$ , and the maximum distortion varies from 0.52 to 1.31 mm $0.52\;{\rm{to}}\;1.31\;{\rm{mm}}$ depending on MRI scanners. For an ROI with a radius of 200 mm centered at the isocenter, the mean magnitude of distortion increases to 0.84 ± 0.45 mm $0.84 \pm 0.45\;{\rm{mm}}$ , and the range of the maximum distortion increases to 1.92 - 5.03 mm $1.92 - 5.03\;{\rm{mm}}$ depending on MRI scanners. The distortion could reach 2 mm at 150 mm from the isocenter., Conclusion: An additional margin to accommodate image distortion should be considered for treatment planning. Imaging with proper patient alignment to the isocenter is vital to reducing image distortion. We recommend performing image distortion checks annually and after major upgrade on MRI scanners., (© 2022 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Background: With advances in systemic therapy translating to improved survival in metastatic malignancies, spine metastases have become an increasingly common source of morbidity. Achieving durable local control (LC) for patients with circumferential epidural disease can be particularly challenging. Circumferential stereotactic body radiotherapy (SBRT) may offer improved LC for circumferential vertebral and/or epidural metastatic spinal disease, but prospective (and retrospective) data are extremely limited. We sought to evaluate the feasibility, toxicity, and cancer control outcomes with this novel approach to circumferential spinal disease., Methods: We retrospectively identified all circumferential SBRT courses delivered between 2013 and 2019 at a tertiary care institution for post-operative or intact spine metastases. Radiotherapy was delivered to 14-27.5 Gy in one to five fractions. Feasibility was assessed by determining the proportion of plans for which ≥95% planning target volume (PTV) was coverable by ≥95% prescription dose. The primary endpoint was 1-year LC. Factors associated with increased likelihood of local failure (LF) were explored. Acute and chronic toxicity were assessed. Detailed dosimetric data were collected., Results: Fifty-eight patients receiving 64 circumferential SBRT courses were identified (median age 61, KPS ≥70, 57% men). With a median follow-up of 15 months, the 12-month local control was 85% (eight events). Five and three recurrences were in the epidural space and bone, respectively. On multivariate analysis, increased PTV and uncontrolled systemic disease were significantly associated with an increased likelihood of LF; ≥95% PTV was covered by ≥95% prescription dose in 94% of the cases. The rate of new or progressive vertebral compression fracture was 8%. There were no myelitis events or any grade 3+ acute or late toxicities., Conclusions: For patients with circumferential disease, circumferential spine SBRT is feasible and may offer excellent LC without significant toxicity. A prospective evaluation of this approach is warranted., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dibs, Palmer, Prasad, Olausson, Bourekas, Boulter, Ayan, Cochran, Marras, Mageswaran, Thomas, Grecula, Guiou, Soghrati, Tili, Raval, Mendel, Scharschmidt, Elder, Lonser, Chakravarti and Blakaj.)

Background: Immune checkpoint inhibitors (ICI) treatment in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) offers new therapeutic venues. We have previously developed a predictive survival model in this patient population based on clinical parameters, and the purpose of this study was to expand the study cohort and internally validate the model., Methods: A single institutional retrospective analysis of R/M HNSCC patients treated with ICI. Clinical parameters collected included p-16 status, hemoglobin (Hb), albumin (Alb), lactate dehydrogenase (LDH), neutrophil, lymphocyte and platelet counts. Cox proportional hazard regression was used to assess the impact of patient characteristics and clinical variables on survival. A nomogram was created using the rms package to generate individualized survival prediction., Results: 201 patients were included, 47 females (23%), 154 males (77%). Median age was 61 years (IQR: 55-68). P-16 negative (66%). Median OS was 12 months (95% CI: 9.4, 14.9). Updated OS model included age, sex, absolute neutrophil count, absolute lymphocyte count, albumin, hemoglobin, LDH, and p-16 status. We stratified patients into three risk groups based on this model at the 0.33 and 0.66 quantiles. Median OS in the optimal risk group reached 23.7 months (CI: 18.5, NR), 13.8 months (CI: 11.1, 20.3) in the average risk group, and 2.3 months (CI: 1.7, 4.4) in the high-risk group. Following internal validation, the discriminatory power of the model reached a c-index of 0.72 and calibration slope of 0.79., Conclusions: Our updated nomogram could assist in the precise selection of patients for which ICI could be beneficial and cost-effective., (© 2022. The Author(s).)

Background: With survival improving in many metastatic malignancies, spine metastases have increasingly become a source of significant morbidity; achieving durable local control (LC) is critical. Stereotactic body radiotherapy (SBRT) may offer improved LC and/or symptom palliation. However, due to setup concerns, SBRT is infrequently offered to patients with ≥3 contiguous involved levels. Because data are limited, we sought to evaluate the feasibility, toxicity, and cancer control outcomes of spine SBRT delivered to ≥3 contiguous levels., Methods: We retrospectively identified all SBRT courses delivered between 2013 and 2019 at a tertiary care institution for postoperative or intact spine metastases. Radiotherapy was delivered to 14-35 Gy in 1-5 fractions. Patients were stratified by whether they received SBRT to 1-2 or ≥3 contiguous levels. The primary endpoint was 1-year LC and was compared between groups. Factors associated with increased likelihood of local failure (LF) were explored. Acute and chronic toxicity was assessed. In-depth dosimetric data were collected., Results: Overall, 165 patients with 194 SBRT courses were identified [54% were men, median age was 61 years, 93% had Karnofsky Performance Status (KPS) ≥70, and median follow-up was 15 months]. One hundred thirteen patients (68%) received treatment to 1-2 and 52 to 3-7 (32%) levels. The 1-year LC was 88% (89% for 1-2 levels vs. 84% for ≥3 levels, p = 0.747). On multivariate analysis, uncontrolled systemic disease was associated with inferior LC for patients with ≥3 treated levels. No other demographic, disease, treatment, or dosimetric variables achieved significance. Rates of new/progressive fracture were equivalent (8% vs. 9.5%, p = 0.839). There were no radiation-induced myelopathy or grade 3+ acute or late toxicities in either group. Coverage of ≥95% of the planning target volume with ≥95% prescription dose was similar between groups (96% 1-2 levels vs. 89% ≥3 levels, p = 0.078)., Conclusions: For patients with ≥3 contiguous involved levels, spine SBRT is feasible and may offer excellent LC without significant toxicity. Prospective evaluation is warranted., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dibs, Blakaj, Prasad, Olausson, Bourekas, Boulter, Ayan, Cochran, Marras, Mageswaran, Thomas, Lee, Grecula, Raval, Mendel, Scharschmidt, Lonser, Chakravarti, Elder and Palmer.)

Background: Radiation-induced hypothyroidism is a common toxicity of head and neck radiation. Our re-planning study aimed to reduce thyroid dose while maintaining target coverage with IMRT., Methods: We retrospectively identified patients with oral-cavity (n = 5) and oropharyngeal cancer (n = 5). Treatment plans were re-optimized with 45 Gy thyroid mean dose constraint, then we cropped the thyroid out of PTVs and further reduced thyroid dose. Target coverage was delivering 100% dose to ≥ 93% of PTV and 95% of dose to > 99% of PTV., Results: Originally, average mean dose to thyroid was 5580 cGy. In model I, this dropped to 4325 cGy (p < 0.0001). In model II, average mean dose was reduced to 3154 cGy (p < 0.0001). For PTV low and PTV int, all had acceptable target coverage., Conclusion: In patients with oral-cavity and oropharyngeal cancers, mean dose could be significantly reduced using a thyroid-optimized or thyroid-sparing IMRT technique with adequate coverage., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Objectives: Neutrophil-lymphocyte ratio (NLR) has been associated with mortality in non-small cell lung cancer (NSCLC), but its association with recurrence in locally advanced NSCLC (LA-NSCLC), specifically, is less established. We hypothesized pre- and posttreatment NLR would be associated with recurrence and mortality., Methods: We studied the association of pretreatment NLR (pre-NLR) and posttreatment NLR at 1 (post-NLR 1 ) and 3 months (post-NLR 3 ) with outcomes in patients with LA-NSCLC treated with chemoradiation. Pre-NLR was dichotomized by 5, an a priori cutoff previously shown to be prognostic in LA-NSCLC. Post-NLR 1 and post-NLR 3 were dichotomized by their medians., Results: We identified 135 patients treated with chemoradiation for LA-NSCLC between 2007 and 2016. Median follow-up for living patients was 61.1 months. On multivariable analysis, pre-NLR ≥ 5 was associated with worse overall survival (HR = 1.82; 95% CI 1.15 - 2.88; p = 0.011), but not with any recurrence, locoregional recurrence, or distant recurrence. Post-NLR 1 ≥ 6.3 was not associated with recurrence or survival. Post-NLR 3 ≥ 6.6 was associated with worse overall survival (HR = 3.27; 95% CI 2.01- 5.31; p < 0.001), any recurrence (HR = 2.50; 95% CI 1.53 - 4.08; p < 0.001), locoregional recurrence (HR = 2.50; 95% CI 1.40 - 4.46; p = 0.002), and distant recurrence (HR = 2.53; 95% CI 1.49 - 4.30; p < 0.001)., Conclusion: Pretreatment NLR is associated with worse overall survival and posttreatment NLR is associated with worse survival and recurrence. These findings should be validated independently and prospectively studied., (Copyright © 2020 Sebastian, Raj, Prasad, Barney, Brownstein, Grecula, Haglund, Xu-Welliver, Williams and Bazan.)

Trans-oral robotic surgery (TORS) has emerged as an important surgical treatment option in the management of human papillomavirus (HPV)-positive and -negative oropharynx cancer. However, treatment selection is paramount to ensure that patients will not require multimodality adjuvant therapy. In this study, we determined predictors of adjuvant therapy in TORS-treated patients. The National Cancer Database (NCDB) was used to identify patients with newly diagnosed clinical T1-T4, N0-N3 oropharyngeal squamous cell carcinoma who underwent TORS between 2010-2016. Kaplan-Meier survival analysis was used to estimate overall survival (OS). A total of 2999 patients were studied, and the five-year OS for the entire cohort was 82.5%, and for HPV-positive and -negative cohorts it was 88.3% and 67.9%, respectively ( p < 0.001). Among all patients treated with TORS, 35.1% of patients received no additional treatment, 33.5% received adjuvant radiation alone (RT), and 31.3% received adjuvant chemoradiation. The N stage was pathologically upstaged in 629 (20.9%) patients after TORS. Patients treated at higher-volume centers were more likely to have negative surgical margins (OR: 0.96, 95% CI: 0.94, 0.98, p < 0.001), but this did not influence the receipt of adjuvant therapy. The high rate of adjuvant multimodality treatment after TORS suggests a need for improved patient selection. Limitations of this study, including lack of data on loco-regional control, progression free survival, acute and late toxicities, and utilization of pretreatment PET/CT imaging, should be addressed in future studies.

Background: Gamma knife (GK) and linear accelerator (LINAC)-based stereotactic radiosurgery (SRS) both offer excellent local control in the management of multiple brain metastases. The efficacy and toxicity of LINAC and GK SRS have not been directly compared in the modern era. We studied outcomes in patients treated with LINAC SRS and GK at two separate institutions., Methods: We identified patients treated with either LINAC or GK who were treated to ≥2 lesions and had available follow up. LINAC patients were treated using single-isocenter multitarget technique. We used Cox regression, Fine and Gray competing risks regression, and nearest neighbor propensity score matching to account for confounders and imbalance between cohorts. Kaplan-Meier curves were used to estimate overall survival and rates of radionecrosis., Results: We identified 391 patients who were treated in 537 courses to a total 2699 lesions (LINAC: 1014, GK: 1685). After propensity score matching, GK was associated with similar overall survival (HR = 0.86; 95% CI 0.59-1.24; p = 0.41) and higher rate of radionecrosis (HR = 3.83; 95% CI 1.66-8.84; p = 0.002) compared to LINAC. In a secondary propensity score matched analysis comparing radionecrosis in single-fraction LINAC and GK, GK remained associated with higher incidence of radionecrosis (HR = 4.42; 95% CI 1.28-15.29; p = 0.019)., Conclusions: In this multi-institutional study, we found similar overall survival with lower incidence of radionecrosis in patients treated with LINAC compared to GK SRS. These findings are hypothesis generating and should be validated in an independent cohort., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: Multiple studies have reported favorable outcomes for stereotactic radiosurgery (SRS) in the treatment of limited brain metastases. An obstacle of SRS in the management of numerous metastases is the longer treatment time using traditional radiosurgery. Single-isocenter multitarget (SIMT) SRS is a novel technique that permits rapid therapy delivery to multiple metastases. There is a lack of clinical evidence regarding its efficacy and safety. We report the outcomes of patients treated with this technique., Methods and Materials: We reviewed the records of patients with intact or resected brain metastases treated with SRS in 1 to 5 fractions using SIMT technique at our institution, with at least 1 available follow-up brain magnetic resonance imaging. Survival, disease control, and toxicity were evaluated using Cox regression, logistic regression, and Kaplan-Meier analysis., Results: We identified 173 patients with 1014 brain metastases. Median follow up was 12.7 months. Median beam-on time was 4.1 minutes. The median dose to the brain was 219.4 cGy. Median overall survival and freedom from intracranial progression were 13.2 and 6.3 months, respectively. Overall survival did not differ between patients treated with greater than or less than 4 lesions (hazard ratio, 1.03; 95% confidence interval 0.66-1.61; P  = .91). Actuarial 1- and 2-year local control were 99.0% and 95.1%, respectively. Rates of grade 2 and grade 3 or higher radionecrosis were 1.4% and 0.9%, respectively., Conclusions: SIMT radiosurgery delivered in 1 to 5 fractions offers excellent local control and acceptable toxicity in the treatment of multiple intact and postoperative brain metastases. This technique should be evaluated prospectively., (© 2019 The Author(s).)

Introduction: Kilovoltge cone beam computed tomography (kV-CBCT) allows for tumor localization and response assessment during definitive chemoradiotherapy for locally advanced NSCLC. We hypothesize that significant tumor volume loss occurs early during radiotherapy and that the extent of volume loss correlates with clinical outcomes., Methods: A total of 52 patients with locally advanced NSCLC treated with definitive chemoradiotherapy were reviewed. kV-CBCT images were used to contour primary gross tumor volumes at four time points during treatment. Patients were dichotomized according to absolute and relative volume changes at each time point. Statistical analyses were performed to evaluate correlations between volume changes and clinical outcomes., Results: The median gross tumor volumes were 77.1, 48.3, 42.5, and 29.9 cm 3 for fractions 1, 11, 21, and final, respectively. Greater relative volume loss between fractions 1 and 21 correlated with improved distant control (hazard ratio [HR] = 0.35, 95% confidence interval [CI]: 0.13-0.94, p = 0.038) and overall survival (HR = 0.40, 95% CI: 0.16-0.98, p = 0.046). Greater relative volume loss between fractions 11 and 21 correlated with improved progression-free survival (HR = 0.39, 95% CI: 0.17-0.88, p = 0.02) and trended toward improved overall survival (HR = 0.43, 95% CI: 0.17-1.06, p = 0.07). On multivariate analysis, greater relative volume loss between fractions 11 and 21 correlated with improved progression-free survival (HR = 0.39, 95% CI: 0.16-0.97, p = 0.041) and overall survival (HR = 0.31, 95% CI: 0.11-0.88, p = 0.027)., Conclusions: Significant primary tumor volume loss occurs early during radiotherapy for locally advanced NSCLC. Greater relative tumor volume loss during treatment correlates with improved disease control and overall survival. Thus, kV-CBCT has potential to be used as a practical prognostic imaging marker., (Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the conventionally fractionated and hypofractionated grid therapy in debulking cervical cancers using the linear quadratic (LQ) model., Methods and Materials: A Monte Carlo technique was used to calculate the dose distribution of a commercially available grid in a 6-MV photon beam. The LQ model was used to evaluate the therapeutic outcome of both the conventionally fractionated (2 Gy/fraction) and hypofractionated (15 Gy/fraction) grid therapy regimens to debulk cervical cancers with different LQ parameters. The equivalent open-field dose (EOD) to the cancer cells and therapeutic ratio (TR) were defined by comparing grid therapy with the open debulking field. The clinical outcomes from 114 patients were used to verify our theoretical model., Results: The cervical cancer and normal tissue cell survival statistics for grid therapy in two regimens were calculated. The EODs and TRs were derived. The EOD was only a fraction of the prescribed dose. The TR was dependent on the prescribed dose and the LQ parameters of both the tumor and normal tissue cells. The grid therapy favors the acutely responding tumors inside radiosensitive normal tissues. Theoretical model predictions were consistent with the clinical outcomes., Conclusions: Grid therapy provided a pronounced therapeutic advantage in both the hypofractionated and conventionally fractionated regimens compared with that seen with single fraction, open debulking field regimens, but the true therapeutic advantage exists only in the hypofractionated grid therapy. The clinical outcomes and our study indicated that a course of open-field radiotherapy is necessary to control tumor growth fully after a grid therapy.

Purpose: Advanced and recurrent tumors of the paranasal sinuses can be difficult to irradiate to high doses with standard external beam radiotherapy (EBRT), conventional brachytherapy, or intraoperative electron beams. We, therefore, explored the role of intraoperative high-dose-rate brachytherapy (IOHDR) as a boost to EBRT in primary tumors or as sole adjuvant treatment in recurrent disease., Methods and Materials: Between 1992 and 1998, 34 patients with locally advanced tumors arising in the paranasal sinuses were treated with IOHDR after maximal surgical excision. Twenty-seven patients with new primaries underwent gross resection and 10-12.5 Gy IOHDR followed by 45-50 Gy EBRT. Seven previously irradiated (45-63 Gy) patients with recurrent disease were treated with 15-20 Gy of IOHDR alone after gross excision. Local control and overall survival were analyzed using the Kaplan-Meier method and compared using the log-rank test., Results: After a mean follow-up of 6 years (range 34-120 months), the 1-, 3-, and 5-year actuarial survival rate was 80%, 62%, and 44%, respectively. The overall local control rate at 1 and 5 years was 75% and 65%, respectively, and distant failure was documented in 44% of patients. Subgroup analysis revealed that the presence of gross disease after surgical resection was the strongest prognosticator, with a 5-year survival and local control rate of 17% and 50%, respectively, compared with 60% and 68%, respectively, for microscopic disease. The local control rates of patients with new primaries were similar to those of patients treated for recurrent disease (63% vs. 71%), probably because gross residual disease occurred only in the group of patients with new primaries. The addition of EBRT to IOHDR increased the 5-year disease-free survival rate from 27% to 44% but had no effect on local control (64% vs. 65%)., Conclusion: IOHDR can be safely used to deliver a high radiation dose to locally advanced and recurrent tumors in the paranasal sinuses. In an attempt to improve outcome, we are now adding limited-dose EBRT (20-30 Gy) after 17.5 Gy of IOHDR in previously irradiated patients and increasing the EBRT dose for both microscopic (50-54 Gy) and gross residual disease (60-65 Gy) after 15 Gy of IOHDR in previously unirradiated patients. Chemosensitization should also be considered in previously irradiated patients and in those with gross residual disease. Interstitial boosting techniques, which can deliver higher doses at depth, should also be considered in patients with gross residual disease.

Primary central nervous system lymphoma (PCNSL) that arises in immune-deficient patients is an aggressive B-cell neoplasm that is universally associated with the EBV. Patients with EBV(+) PCNSL face a particularly poor prognosis with median survival times of 2-12 months despite aggressive management with radiation therapy. We have developed a preclinical model of EBV(+) PCNSL to explore strategies that specifically target EBV-infected B lymphoblasts in vivo. Stereotactic implantation of EBV-transformed human lymphoblastoid B-cell lines into the caudate nucleus of the nude rat resulted in lethal CNS tumor burden manifested by the onset of focal neurological symptoms within 21 days. Histological evaluation at autopsy revealed a multifocal, perivascular human EBV(+) lymphoblastic B-cell infiltrate that displayed a latency type III EBV gene expression profile similar to PCNSL that develops in some immune-deficient patients. Radiation (1600 cGy) of lymphoblastoid B-cell lines resulted in up-regulation of the EBV thymidine kinase (EBV-TK) transcript and sensitization of these cells to drug-induced apoptosis using nucleoside analogs. Enhanced expression of EBV-TK mRNA in EBV(+) PCNSL tumors by radiation therapy occurred in a dose-dependent fashion. In vivo trials using the nude rat PCNSL model demonstrated significantly improved mean survival time (MST) with single fraction whole-brain radiotherapy (WBRT) and antiviral therapy consisting of zidovudine (AZT) and ganciclovir (GCV; MST 41.3 +/- 3.3 days; P = 0.05), compared with either antiviral therapy (MST 32.1 +/- 1.1 days) or WBRT alone (MST 22 +/- 0.8 days). We found constitutive and abundant EBV-TK mRNA expression in a stereotactic core biopsy specimen from a solid organ transplant patient with EBV(+) PCNSL. Withdrawal of immunosuppression did not result in disease regression. This patient achieved a complete response after therapy with high-dose AZT and GCV in the absence of WBRT, and remains in remission on oral maintenance AZT/GCV therapy 3 years after diagnosis. These results suggest that antiviral therapies can be effectively explored in vivo using a preclinical animal model of human EBV(+) PCNSL with subsequent translation to patients with EBV(+) PCNSL.